title: Calreticulin exposure on malignant blasts predicts a cellular anticancer immune response in patients with acute myeloid leukemia.
abstract: Experiments performed in mice revealed that anthracyclines stimulate immunogenic cell death that is characterized by the pre-apoptotic exposure of calreticulin (CRT) on the surface of dying tumor cells. Here, we determined whether CRT exposure at the cell surface (ecto-CRT) occurs in human cancer in response to anthracyclines in vivo, focusing on acute myeloid leukemia (AML), which is currently treated with a combination of aracytine and anthracyclines. Most of the patients benefit from the induction chemotherapy but relapse within 1-12 months. In this study, we investigated ecto-CRT expression on malignant blasts before and after induction chemotherapy. We observed that leukemic cells from some patients exhibited ecto-CRT regardless of chemotherapy and that this parameter was not modulated by in vivo chemotherapy. Ecto-CRT correlated with the presence of phosphorylated eIF2α within the blasts, in line with the possibility that CRT exposure results from an endoplasmic reticulum stress response. Importantly, high levels of ecto-CRT on malignant myeloblasts positively correlated with the ability of autologous T cells to secrete interferon-γ on stimulation with blast-derived dendritic cell. We conclude that the presence of ecto-CRT on leukemia cells facilitates cellular anticancer immune responses in AML patients.
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, Villejuif, France.
authors.forename: M
authors.initials: M
authors.lastname: Wemeau
authors.forename: O
authors.initials: O
authors.lastname: Kepp
authors.forename: A
authors.initials: A
authors.lastname: Tesnière
authors.forename: T
authors.initials: T
authors.lastname: Panaretakis
authors.forename: C
authors.initials: C
authors.lastname: Flament
authors.forename: S
authors.initials: S
authors.lastname: De Botton
authors.forename: L
authors.initials: L
authors.lastname: Zitvogel
authors.forename: G
authors.initials: G
authors.lastname: Kroemer
authors.forename: N
authors.initials: N
authors.lastname: Chaput
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018943:Anthracyclines / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D037282:Calreticulin / Q000187:drug effects / Q000378:metabolism*; D015331:Cohort Studies; D003713:Dendritic Cells / Q000502:physiology; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism; D005260:Female; D006801:Humans; D007111:Immunity, Cellular / Q000187:drug effects; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008297:Male; D008875:Middle Aged; D010587:Phagocytosis / Q000187:drug effects; D010766:Phosphorylation; D016019:Survival Analysis; D013601:T-Lymphocytes / Q000276:immunology
chemical_list: D018943:Anthracyclines; D000970:Antineoplastic Agents; D037282:Calreticulin; D015852:Eukaryotic Initiation Factor-2